A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mPR alpha-PGRMC2 receptor complex (Thomas 2013), which is accompanied by heme binding (Rohe 2009), and may therefore result in a heme drain. A decreased cellular heme pool may then upregulate ALAS-1 (Besur 2014). In addition, the heme-sensing receptor, Rev-erb-alpha, will sense the decreased level of the regulatory heme pool and reduce its repressor effect on PGC-1 alpha (Wu 2009). PGC-1 alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005). An in vitro study found that estrogens might directly activate ALAS-1 (Du Plessis 2009). In the presence of estrogen, the estrogen receptor-alpha (ER-alpha) binds to estrogen receptor elements (ERE) in the ALAS-1 promotor and results in an elevated transcription of ALAS-1 and thereby causing a subsequent increase in the rate of the entire heme biosynthesis pathway.

Estrogens and progestogens are considered as potentially porphyrinogenic substances and are known to have caused porphyric attacks in susceptible carriers of acute porphyria. Both pharmacodynamic and pharmacokinetic properties can explain the triggering effect in acute porphyria. Studies have shown that these hormones can affect CYP enzymes by induction and mechanism-based inhibition. Although these effects are described to a limited extent in drug-drug interactions studies in general, it is likely that they have a role in a probable upregulation of the heme biosynthesis.

Ethinyl estradiol is a synthetic 20-acetylenic estradiol derivative. Norgestimate is a 19-nortestosterone derivate.

Fixed-dose combined oral contraceptive. The half-life of norgestimate is about 30-67 hours, and the half-life of ethinyl estradiol is about 24 hours. Norgestimate ia a prodrug and is rapidly converted to the active metabolites norelgestromin and norgestrel (the levorotatory form is most biologically active) (Schindler 2008, SPC).

Ethinyl estradiol is mainly metabolized via hydroxylation by CYP3A4 and CYP2C9 (Guengerich 1990, Wang 2004). Ethinyl estradiol is listed as an activator of hPXR by several references (Honkakoski 2003, Kretschmer 2005, Mnif 2007), but one in vitro study found that ethinyl estradiol only moderately transactivate hPXR, and this was seen at concentrations > 10 µM (Zhang 2007). Since this is well above concentrations obtained clinically the authors concluded that PXR activation is unlikely to be clinically relevant. Ethinyl estradiol contains an acetylenic group that has shown to cause mechanism-based inactivation of CYP enzymes (Ortiz 1980). In vitro studies suggest that ethinyl estradiol is a mechanism-based inhibitor of CYP3A4 through covalent attachment of the modified heme to the apoprotein (Guengerich 1988, Lin 2002) and CYP2B6 (Kent 2002). In vivo studies showed only minor and clinically insignificant effects on CYP 3A4 activity by oral contraceptives containing ethinylestradiol and progestin (Belle 2002, Palovaara 2000). The lack of observed significant effects on CYP 3A4 in vivo may partly be explained by PXR induction being counteracted and masked by a concurrent CYP inhibition, and this phenomenon has been discussed by Wei et al. for other drugs (Wei 2016). Ethinyl estradiol was found to be an in vitro inhibitor of CYP2C9 and CYP2C19 (Laine 2003), and the CYP2C19 inhibitory action is supported by in vivo studies (Hägg 2001, Palovaara 2003). Norgestimate is rapidly metabolised by first-pass (intestinal and/or hepatic) mechanisms to norelgestromin. Norelgestromin is further metabolized in the liver to norgestrel/levonorgestrel, as well as to other hydroxylated and conjugated metabolites (SPC). Both norelgestromin and norgestrel is metabolized by CYP3A4, with minor contributions from CYP2B6 and CYP2C9 (Ahire 2017). In vitro studies have shown that norgestimate and the metabolite levonorgestrel has potential to inhibit CYP3A4, and it is suggested that the inhibition could be mechanism-based (Back 1991). Progesterone and synthetic progestogens activate PXR (Kliewer 1998). Progestogens and estradiol are not listed as significant inducers of CYP 3A4 in most interaction databases (Preissner 2010, NOMA, Lexi-Interact, The Danish Health and Medicines Authority, Micromedex). Results from clinical studies suggest that the increased hormonal levels in pregnancy have the potential to alter hepatic cytochrome P450 drug metabolism (Anderson 2005). Also, in vitro studies have shown increased CYP mRNA after exposing hepatocytes to progesterone and estradiol levels equal to the high hormonal levels typically seen in the third trimester of pregnancy (Choi 2013). Hormonal therapy generally leads to a much lower plasma concentration relative to the levels of endogenous hormones in pregnancy and may explain the lack of observed significant effects of administered hormones on CYP 3A4 in vivo. However, since both ethinyl estradiol and the progestin component have the potential to induce ALAS1 through PXR activation and at the same time cause mechanism-based inhibition of CYP 3A4, this may explain the absence of observed pharmacokinetic drug-drug interactions. For an evaluation of the porphyrinogenicity of these drugs it is important to realize that the inhibitory effect can mask the inductive power and that an increased de novo synthesis of CYP3A4 can take place irrespective of negative results from in vivo DDI-studies. The effects of concomitant induction and inhibition have in general been discussed by Wei et al. for other drugs (Wei 2016). Since CYP3A4 quantitatively is the largest CYP isoenzyme, an increased de novo synthesis of CYP3A4, although masked, will give an upregulation of ALAS-1and thereby a higher flux through the heme biosynthesis. Such a mechanism can possibly in part explain the observed porphyrinogenic effects of these drugs. Studies have shown that women with acute porphyria have an altered 5alfa-reductase steroid metabolism and it is suggested that this may lead to a diversion from the 5 alfa reductase pathway to formation of 5beta steroid metabolites that may be more potent inductors of ALAS1 (Innala 2012, Anderson 1979, Jacobs 2005).

It is from clinical observations well known that progestogens and estrogens have a role in precipitating acute porphyric attacks (Andersson 2003, Kauppinen 1992, Bonkovsky 2014).